Traveling through Coahoma, Quitman, Panola counties, it has a length of 43.9 miles (70.7 km) and connects Clarksdale, Hopson, Lambert, and Crowder.

The highway heads due east and enters the city limits of Clarksdale, but travels to the west and south of the downtown area.

MS 322 exits the freeway at the interchange with US 49 and then runs concurrent with it to the southeast for about one-half mile (0.80 km) in the community of Hopson.

Near the center of town, MS 322 takes a one-block jog north on Quitman Avenue before resuming an easterly course on 2nd Street.

Except along its concurrencies with U.S. highways around Clarksdale, the entire road is two lanes wide and is fully state-maintained.